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Is the general feeling that those who will be diagnosed 5 years from today will benefit greatly from todays drug pipeline and perhaps never see any significant disability? It seems as if the scientific community has learned more about MS over the past 10 years than the past 100 years prior to that and hopefully one of the drugs in dignan's pipeline is the breakthrough that stops MS progression (and not just reduces relapses by 30%).

Or is it more likely that we will have to wait 15 - 20 years for stem cell therapy or some other magic bullet drug?

I'm a 33-yr old male and have been married just over 1 year. I want some assurance that my future kids will likely never have MS.

Brownsfan,

I don't think any of us can see into the future, but here's my take (which may be completely wrong).

- More people will get this disease i.e. the rates are increasing. This will increase the pressure on Govs to fund more research / find some answers etc.

- IT / computer power is growing at unbelievable rates so better data analysis, identification of the genes involved, modelling of the disease process etc (rather than mice).

- Better imaging tools e.g. will give a clearer picutre of what is going on / and better assessment of the effectiveness of treatments etc.

- Research in other areas (neurological diseases / cancer / immune system) will have read across to MS.

- Stem cell therapies will be refined and be used to repair damage.

- Neuro-protective treatments will protect the CNS from damage.


So overall, the future has to look better. Within ten years there should be strategies in place to contain the disease and limit disability. This may well include better anti-inflammatory drugs, neuro-protective drugs, supplements (such as Vit D).


But I don't believe this disease will be cured in the next 20 years - in the sense of ridding our bodies of it. This disease, I suspect, will turn out to be a variety of different diseases, with different triggers etc etc.


So in my view, a mixed picture, but 2015 should be a better time all round for those diagnosed with MS. Recent reports suggest that most cancers will be chronic illnesses within the next ten years. Diabetes, using stem cells, is another disease that may be 'curable' within ten years. Parkinsons will probably be the first neurological disease to be 'cured' through stem cells, as the damage tends to be in one part of the brain.

Stem cells as a treatment for MS is much further away (I think). Damage / black holes throughout the CNS is the problem. MS is the classic disease where prevention is better than cure. Hopefully, prevention strategies will be developed as more is known about possible causes.

But one has to remember that at the start of every decade an announcement is made that MS will be cured by the end of the decade. Many false dawns to date. This disease has a nasty habit of having something else up its sleeve just as the researchers think they have fathomed it out.

Hope this helps in some way.

Ian

bromley wrote:This disease, I suspect, will turn out to be a variety of different diseases, with different triggers etc etc.

Quite agree Ian, it aint one size fits all and I'm quite sure there wont be a one size fits all cure.

I think it's been summed up pretty well. My two bits is that we are seeing steady, constantly accelerating progress on substances being tested for MS in clinincal trials. I'm not entirely certain of this, but I believe there have never been nearly this many substances in phase I, II or III being targeted at MS.

So far, we have seen nothing come out the end of the pipeline in years. Tysabri might change that (again) in 2006. But then we're in for another drought for the rest of 2006 and 2007. Hopefully 2008 is when new treatments start getting approved again, and I believe we are unlikely to go a calendar year after that where there isn't a new treatment approved.

So if I had to guess, I'd say there is going to be increased frustration among us MS sufferers over the next 2 years as we wait...and wait...but 5 years from now the picture will be much improved, and will be improving rapidly by that time I think (hope). I don't think it will be at the stage where a person diagnosed with MS has nothing to worry about, but it will be somewhat less worrying than it is today I hope.

All of this applies mostly to RRMS, but I'm optimistic that some of the treatments currently being tested for SPMS and PPMS will be successful, maybe within 5 years.

One more question - why does it take so long for a drug to emerge from Phase III trials? Hypothetically, if something appears to work (like maybe FTY720) wouldn't 1-2 years be sufficient time to evaluate safety and efficacy to at least roll the drug out to those who truly need it? 1 or 2 years can mean the world to some of us.

Brownsfan,

I echo Dignan's post about timings - definitely a drought after 2006 for a few years.

There is a chance of some treatments coming on stream which are already licensed. The UK MS society is funding a trial (neuro-protective treatment) of a drug already used for other purposes.

Maybe Vit D supplements, or minocycline, might be shown to have beneficial effects and these are already available.

Phase III trials do seem to take a long time. Even after the two year trial there is a long review process etc. The US system seems to be quicker than Europe.

But a major influence is the CRAB manufacturers. There are some 160 MS treatment trials underway, but the bulk of these relate to the current four CRAB drugs either head-to-head trials or follow-on trials. These companies are not going to give up on these expensive and relatively ineffective treatments. Any trial for a new RR treatment has to find trialists which is tough, given that those dx'd will have been told to go on a CRAB drug. I have little faith in the claims of the manufacturers that they want to improve the lot of those with this disease.

But 2006 could be interesting. If Tysabri is introduced, proves popular, more effective and safe (although there are bound to be some issues that arise), then the CRAB manufacturers could find themselves in a more competitive market. I think we will see oral treatments coming to market more quickly if Tysabri is re-introduced.

Another good point Bromley, some of the trials of nutritional supplements -- N-aceytl-cysteine, alpha lipoic acid, vitamin D etc -- could prove to be helpful in larger human trials in the next couple of years. As you say, minocycline, and doxycycline could finish their trials in the next couple of years. And then there are the statins, particularly simvastatin (zocor) and atorvastatin (lipitor). I think those trials started in 2003, or at the latest in early 2004, and they are just phase II trials, so they should have something to share with the world some time in 2006.

I am guessing that the MS breakthrough will come from an "unexpected" and unsung area (at least for MS) - biochemical genetics, for lack of a better description. It is my gut feeling (and bias) that MS, or at least some forms of MS, is ultimately a multi-factorial metabolic disease, with immunological components, but the root problem is not immunological. I've spent some time poking through case reports of weird and rare inherited metabolic diseases that have both neurological (particularly demyelination and dysmyelination as features) and immunological (autoimmunity, infection persistence, etc). There is an amazing amount of work out there that is leading to rapid gene mapping and location of specific mutations for these rare diseases.

What puzzles me with MS research is that so much of the general clinical observation, measurement of vitamin levels, enzyme activity, etc was done decades ago (before it was decided MS was an autoimmune disease), and little of it is being revisited in light of current state of knowledge of metabolism and genetics. What has been done recently, even if it shows significant differences (like biotin), has been seemingly ignored.

The first area that may push biochemical genetics over into the MS world might actually be cardiovascular disease (CVD). CVD is really common, and there is a lot of emerging work on the genetics of CVD and diet and medication recommendations based on genetic profiles to prevent CVD development. If one of the factors in MS involves lipid metabolism, which I strongly suspect is the case, some of this thinking and approach might - eventually - edge its way into MS treatment and prevention.

It is my hope that MS gets some fresh avenues of exploration.

It is my guess that, near-term, incremental clinical breakthroughs will come initially through off-label use of nonMS drugs rather than through a trial of a new drug.
Lisa

Lisa,

Thanks for this post. I agree with you that the MS research world has been sucked into the auto-immune mindset for too long. They've formed a mouse model based on this theory which has yet to deliver.

I suspect, like you, that a breakthough will come elsewhere. Let's hope so.

Once other scientists have made a breakthrough and we are free from this disease (or relatively free from this disease) I will organise a Nuremberg style trial at which all the so called MS experts will be asked to account for the last 60 years and £x billion spent. They will be forced to hand back all the awards they have received and their pensions will be stiopped. All the money recovered will help compensate all those who have suffered and buy a nice new home for all those mice whose relatives have been butchered for no reason).

As you can see I'm having a bad start to the week.

Ian

Ian, can we call the inquisition "Neuro-burg"? I have a couple docs that I'd like to see front and center .

Lisabee, per your comments, I am particularly puzzled as to why Dr. Roy Swank's 30+ years of research implicating a link between diet and MS have been completely dismissed.

Lisa,

You wrote that progress with this disease might come from a different area.

I started a discussion recently about viruses and MS and how Canadian researchers had shown that children with MS were much more likley to have had EBV than children withoun MS.

Here is an article, not about MS, but about infections and cancer.

http://news.bbc.co.uk/1/hi/health/4521024.stm

Maybe we should give cancer researchers a go at MS - they can't do any worse than the MS researchers.

Ian

Brownsfan and bromley,

I am also a bit puzzled why Dr. Swank's observations of benefit of low-fat diets have not gotten a closer look. The problem with dietary studies is they can't be blinded for a clinical trial. Studies with supplements can be blinded and placebo-controlled, but the participant is always aware of changing diet unless the study gives participants mystery pre-packaged foods - and no one is going to want to spend years, even months, eating like that. I think changing my diet in some manners similar to Dr. Swank's recommendations has helped my overall health and symptoms possibly relating to MS. But of course I'm biased on that point! One possibility for studying diet influences is to use the parameters measured in cardiovascular studies, and see if diet changes improve lipid profiles (or other clinical chemistry), and if that objective measure has any influence on MS symptoms. Such a study could be a two-for-one, with both MS and cardio information generated.

The recent additional inspiration for my own diet change was some cardiovascular blood work I had done, which showed I had a genetic risk factor for cardiovascular disease (apoproteinE 4 allele; the "normal" allele is designated ApoE 3). Having this allele and its association with MS has been investigated already, because it is more common in people of northern European descent compared to southern Europeans and that got some researchers excited enough to look at MS associations. (ApoE4 is also more common in some aboriginal populations outside Europe, and there is interesting anthropology-related studies suggesting the ApoE 4 is the original "wild-type" allele from pre-agricultural days. That is a whole other post!) Researchers have shown having an ApoE 4 doesn't make it more likely to get MS, but some studies have shown having it makes the MS progression worse, which wasn't cheerful news. My blood lipid profile was actually not that bad given the genetic propensity for it, probably because I had already modified my diet for a year prior to the blood work. It gave me incentive to try a low-dose statin plus sustained release niacin to improve my LDL:HDL ratios. The jury is still out, but I find that I'm suddenly feeling much better and mentally sharper. I'm not sure if it is the statin, the pharmacological-dose niacin doing something else (that tryptophan tie-in) or just coincidence. I'll get more cardio blood work done in March or April to follow up. Changes in blood chemistry are objective measurements and it will be interesting to see if anything correlates with subjective ones. In the meantime, I will look into both lipids and tryptophan and start new posts.

Here's an interesting abstract from PubMed, published in Nature October of this year. It shows one of the tie-ins between lipid metabolism (potentially diet-influenced) and immunological function. How it relates exactly to MS I don't know but something tells me it might be important on both diet and infection angles:

Apolipoprotein-mediated pathways of lipid antigen presentation.

van den Elzen P, Garg S, Leon L, Brigl M, Leadbetter EA, Gumperz JE, Dascher CC, Cheng TY, Sacks FM, Illarionov PA, Besra GS, Kent SC, Moody DB, Brenner MB.

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

Peptide antigens are presented to T cells by major histocompatibility complex (MHC) molecules, with endogenous peptides presented by MHC class I and exogenous peptides presented by MHC class II. In contrast to the MHC system, CD1 molecules bind lipid antigens that are presented at the antigen-presenting cell (APC) surface to lipid antigen-reactive T cells. Because CD1 molecules survey endocytic compartments, it is self-evident that they encounter antigens from extracellular sources. However, the mechanisms of exogenous lipid antigen delivery to CD1-antigen-loading compartments are not known. Serum apolipoproteins are mediators of extracellular lipid transport for metabolic needs. Here we define the pathways mediating markedly efficient exogenous lipid antigen delivery by apolipoproteins to achieve T-cell activation. Apolipoprotein E binds lipid antigens and delivers them by receptor-mediated uptake into endosomal compartments containing CD1 in APCs. Apolipoprotein E mediates the presentation of serum-borne lipid antigens and can be secreted by APCs as a mechanism to survey the local environment to capture antigens or to transfer microbial lipids from infected cells to bystander APCs. Thus, the immune system has co-opted a component of lipid metabolism to develop immunological responses to lipid antigens.

PMID: 16208376 [PubMed - indexed for MEDLINE

^^^^^^^^^

Ian, I'm interested in the infectious angle too, particularly why it seems people with MS, or at least some people with MS, seem to have evidence of persisting infections or associations with certain infections. Why is that??? What is the susceptibility factor? I have gotten interested in weird inherited metabolic diseases in which (usually) infants with the disease have not only severe myelin disorders but also persistent infections they can't clear. What if some people with MS are heterozygous (carriers) for some of these rare recessive diseases, such that evidence of a partial enzyme disorder doesn't show up until much later in life?

The oncology paper you cited was interesting in discussing associations with cancer and viral infections in susceptible people. Years ago when I was in grad school it was known that certain viruses could induce cancers in lab animals, but there was no "human evidence" that viruses cause cancer in humans. That thinking has certainly changed. And there is some epi evidence that like the cancer clusters, MS seemingly "spreads" - not that MS itself is infectious, but that a relatively common infection moving through a population will cause some people to develop MS. I'll see if I can find that abstract again, I think it was a Swedish study.

Lisa

LisaBee wrote:The recent additional inspiration for my own diet change was some cardiovascular blood work I had done, which showed I had a genetic risk factor for cardiovascular disease (apoproteinE 4 allele; the "normal" allele is designated ApoE 3).

Lisa, this information may be of interest to you. David Perlmutter, author of the Better Brain Book states that ApoE4 is associated with an increased risk for alzheimer's disease. He states that ApoE2 & 3 are the normal alleles. People with these alleles have a 20% risk of developing alzheimer's by the age of 80. However, people who have one copy (heterozygous) of ApoE4 have a 47% risk and those with 2 copies (homozygous) have a 91% risk.

Here's yet another reason to supplement with turmeric...

• Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo.
  J Biol Chem. 2005 Feb 18;280(7):5892-901.

In vivo studies showed that curcumin injected peripherally into aged Tg mice crossed the blood-brain barrier and bound plaques. When fed to aged Tg2576 mice with advanced amyloid accumulation, curcumin labeled plaques and reduced amyloid levels and plaque burden. Hence, curcumin directly binds small beta-amyloid species to block aggregation and fibril formation in vitro and in vivo. These data suggest that low dose curcumin effectively disaggregates Abeta as well as prevents fibril and oligomer formation, supporting the rationale for curcumin use in clinical trials preventing or treating AD.

NHE

NHE,

Thanks for the post. I have gotten interested in the ApoE 4 and all of its negative associations, including late-onset Alzheimer's risk. Since I have MS, late-onset Alzheimer's is not much of a personal worry anymore - given the progress of MS research I won't live long enough. But the Alzeimer's link is extremely interesting.

I am a Apo E 3/4, so I have one of each. It is not rare, I think about 25% of the US population has at least one 4, and I read a paper from Denmark where 45-50% of the population has at least one 4, although I looked again and couldn't find it, the papers I saw had about 17% so I could be wrong. There are more ApoE 4 carriers in northern than in southern Europe. Conversely, about 40% of African pygmies have the ApoE 4, and it is apparently high in some other aboriginal subSaharan African populations. There is actually some indication that the ApoE 4 is, evolutionarily speaking, an "older" allele; it has been found in chimps. There is also anthropological suggestions that the 4 is the original "wild-type" allele in humans, and that the 3's are more predominant in populations where human agriculture has been practiced the longest. This has some interesting implications, that maybe the ApoE 4 is one of the "thrifty genes" that interfaces poorly with with the modern diet. The clinic that did my bloodwork indcated people with ApoE 4's are the most highly responsive to dietary changes, at least as far as blood lipids go.

The burning personal question I have is whether the ApoE 4 is in itself a "bad" allele, or it is only bad in connection with the modern diet. It will be interesting to see if people with this allele who modify their diet to correct the blood lipid problems will have a reduced risk of both cardiovascular disease and Alzheimer's, also, whether it mitigates some of the MS progression that appears worse in carriers of the allele. There is no data on that yet, but I hope someone is doing a study with subjects willing to change their diet - it will require long-term followup of decades.

I am sometimes pitifully optimistic, and also keep my eye for ANY suggested positive aspects of having an ApoE 4 allele, given its bad rap. There is some recent information that people with the ApoE 4 have a superior Vitamin K status, and ApoE 2 and ApoE 4's have less severe liver damage from hepatitis C than people with ApoE 3's only. That's not much counterweigh yett, but it is something!

Turmeric is looking helpful!

Lisa

LisaBee wrote:It will be interesting to see if people with this allele who modify their diet to correct the blood lipid problems will have a reduced risk of both cardiovascular disease and Alzheimer's

The following paper doesn't address your ApoE4 allele/diet question. However, it does indicate that omega-3 supplementation shows potential for helping with Alzheimer's disease. I should also note that this is just one paper of many available on this subject via PubMed.

• A diet enriched with the omega-3 fatty acid docosahexaenoic acid reduces amyloid burden in an aged Alzheimer mouse model.
  Neurosci. 2005 Mar 23;25(12):3032-40.

Epidemiological studies suggest that increased intake of the omega-3 (n-3) polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) is associated with reduced risk of Alzheimer's disease (AD). DHA levels are lower in serum and brains of AD patients, which could result from low dietary intake and/or PUFA oxidation. Because effects of DHA on Alzheimer pathogenesis, particularly on amyloidosis, are unknown, we used the APPsw (Tg2576) transgenic mouse model to evaluate the impact of dietary DHA on amyloid precursor protein (APP) processing and amyloid burden. Aged animals (17-19 months old) were placed in one of three groups until 22.5 months of age: control (0.09% DHA), low-DHA (0%), or high-DHA (0.6%) chow. beta-Amyloid (Abeta) ELISA of the detergent-insoluble extract of cortical homogenates showed that DHA-enriched diets significantly reduced total Abeta by >70% when compared with low-DHA or control chow diets. Dietary DHA also decreased Abeta42 levels below those seen with control chow. Image analysis of brain sections with an antibody against Abeta (amino acids 1-13) revealed that overall plaque burden was significantly reduced by 40.3%, with the largest reductions (40-50%) in the hippocampus and parietal cortex. DHA modulated APP processing by decreasing both alpha- and beta-APP C-terminal fragment products and full-length APP. BACE1 (beta-secretase activity of the beta-site APP-cleaving enzyme), ApoE (apolipoprotein E), and transthyretin gene expression were unchanged with the high-DHA diet. Together, these results suggest that dietary DHA could be protective against beta-amyloid production, accumulation, and potential downstream toxicity.

One of the other papers I alluded to above indicates that DHA may offer neuroprotection against amyloid beta plaques by acting as a substrate for the production of neuroprotectin D1 which seems to counteract the effects of amyloid beta.

Deficiency in docosahexaenoic acid (DHA), a brain-essential omega-3 fatty acid, is associated with cognitive decline. Here we report that, in cytokine-stressed human neural cells, DHA attenuates amyloid-beta (Abeta) secretion, an effect accompanied by the formation of NPD1, a novel, DHA-derived 10,17S-docosatriene. DHA and NPD1 were reduced in Alzheimer disease (AD) hippocampal cornu ammonis region 1, but not in the thalamus or occipital lobes from the same brains. The expression of key enzymes in NPD1 biosynthesis, cytosolic phospholipase A2 and 15-lipoxygenase, was altered in AD hippocampus. NPD1 repressed Abeta42-triggered activation of proinflammatory genes while upregulating the antiapoptotic genes encoding Bcl-2, Bcl-xl, and Bfl-1(A1). Soluble amyloid precursor protein-alpha stimulated NPD1 biosynthesis from DHA. These results indicate that NPD1 promotes brain cell survival via the induction of antiapoptotic and neuroprotective gene-expression programs that suppress Abeta42-induced neurotoxicity.

NHE